Matching Items (13)
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- All Subjects: Addiction
- Creators: Neisewander, Janet
- Creators: Department of Supply Chain Management
- Member of: Theses and Dissertations
Description
Intermittent social defeat stress induces cross-sensitization to psychostimulants and escalation of drug self-administration. These behaviors could result from the stress-induced neuroadaptation in the mesocorticolimbic dopamine circuit. Brain-derived neurotrophic factor (BDNF) in the ventral tegmental area (VTA) is persistently elevated after social defeat stress, and may contribute to the stress-induced neuroadaptation in the mesocorticolimbic dopamine circuit. BDNF modulates synaptic plasticity, and facilitates stress- and drug-induced neuroadaptations in the mesocorticolimbic system. The present research examined the role of mesolimbic BDNF signaling in social defeat stress-induced cross-sensitization to psychostimulants and the escalation of cocaine self-administration in rats. We measured drug taking behavior with the acquisition, progressive ratio, and binge paradigms during self-administration. With BDNF overexpression in the ventral tegmental area (VTA), single social defeat stress-induced cross-sensitization to amphetamine (AMPH) was significantly potentiated. VTA-BDNF overexpression also facilitates acquisition of cocaine self-administration, and a positive correlation between the level of VTA BDNF and drug intake during 12 hour binge was observed. We also found significant increase of DeltaFosB expression in the nucleus accumbens (NAc), the projection area of the VTA, in rats received intra-VTA BDNF overexpression. We therefore examined whether BDNF signaling in the NAc is important for social defeat stress-induced cross-sensitization by knockdown of the receptor of BDNF (neurotrophin tyrosine kinase receptor type 2, TrkB) there. NAc TrkB knockdown prevented social defeat stress-induced cross-sensitization to psychostimulant. Also social defeat stress-induced increase of DeltaFosB in the NAc was prevented by TrkB knockdown. Several other factors up-regulated by stress, such as the GluA1 subunit of Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and BDNF in the VTA were also prevented. We conclude that BDNF signaling in the VTA increases social defeat stress-induced vulnerability to psychostimulants, manifested as potentiated cross-sensitization/sensitization to AMPH and escalation of cocaine self-administration. Also BDNF signaling in the NAc is necessary for the stress-induced neuroadaptation and behavioral sensitization to psychostimulants. Therefore, TrkB in the NAc could be a therapeutic target to prevent stress-induced vulnerability to drugs of abuse in the future. DeltaFosB in the NAc shell could be a neural substrate underlying persistent cross-sensitization and augmented cocaine self-administration induced by social defeat stress.
ContributorsWang, Junshi (Author) / Hammer, Ronald (Thesis advisor) / Feuerstein, Burt (Committee member) / Nikulina, Ella (Committee member) / Neisewander, Janet (Committee member) / Arizona State University (Publisher)
Created2013
Description
The current model of revenue generation for some free to play video games is preventing the companies controlling them from growing, but with a few changes in approach these issues could be alleviated. A new style of video games, called a MOBA (Massive Online Battle Arena) has emerged in the past few years bringing with it a new style of generating wealth. Contrary to past gaming models, where users must either purchase the game outright, view advertisements, or purchase items to gain a competitive advantage, MOBAs require no payment of any kind. These are free to play computer games that provides users with all the tools necessary to compete with anyone free of charge; no advantages can be purchased in this game. This leaves the only way for users to provide money to the company through optional purchases of purely aesthetic items, only to be purchased if the buyer wishes to see their character in a different set of attire. The genre’s best in show—called League of Legends, or LOL—has spearheaded this method of revenue-generation. Fortunately for LOL, its level of popularity has reached levels never seen in video games: the world championships had more viewers than game 7 of the NBA Finals (Dorsey). The player base alone is enough to keep the company afloat currently, but the fact that they only convert 3.75% of the players into revenue is alarming. Each player brings the company an average of $1.32, or 30% of what some other free to play games earn per user (Comparing MMO). It is this low per player income that has caused Riot Games, the developer of LOL, to state that their e-sports division is not currently profitable. To resolve this issue, LOL must take on a more aggressive marketing plan. Advertisements for the NBA Finals cost $460,000 for 30 seconds, and LOL should aim for ads in this range (Lombardo). With an average of 3 million people logged on at any time, 90% of the players being male and 85% being between the ages of 16 and 30, advertising via this game would appeal to many companies, making a deal easy to strike (LOL infographic 2012). The idea also appeals to players: 81% of players surveyed said that an advertisement on the client that allows for the option to place an order would improve or not impact their experience. Moving forward with this, the gaming client would be updated to contain both an option to order pizza and an advertisement for Mountain Dew. This type of advertising was determined based on community responses through a sequence of survey questions. These small adjustments to the game would allow LOL to generate enough income for Riot Games to expand into other areas of the e-sports industry.
ContributorsSeip, Patrick (Co-author) / Zhao, BoNing (Co-author) / Kashiwagi, Dean (Thesis director) / Kashiwagi, Jacob (Committee member) / Barrett, The Honors College (Contributor) / Sandra Day O'Connor College of Law (Contributor) / Department of Economics (Contributor) / Department of Supply Chain Management (Contributor)
Created2015-05
Description
Drug addiction is a pervasive problem in society, as it produces major increases in health care costs, crime, and loss of productivity. With over 3 million long-term users in America alone, cocaine is one of the most identifiable and addictive drugs. Cocaine produces major neurological changes in the central nervous system, including widespread changes in gene expression. MicroRNAs are small, non-coding transcripts that regulate gene expression post-transcriptionally by preventing translation into function protein. Given that one miRNA can target several genes simultaneously, they have the potential to attenuate drug-induced changes in gene expression. We previously found that the microRNA miR-495 regulates several addiction-related genes (ARGs) and is highly expressed in the nucleus accumbens (NAc), an important brain region involved in reward and motivation. Furthermore, acute cocaine decreases miR-495 expression and increases ARG expression in the NAc. Therefore, the aim of this thesis was to determine the effect of miR-495 overexpression in the NAc on cocaine self-administration behavior. Male Sprague Dawley rats were trained to lever press for cocaine and were then infused with a lentivirus into the NAc that either overexpressed green fluorescent protein (GFP, control) or miR-495+GFP. We then tested the rats on several doses of cocaine on both a fixed ratio (5) and progressive ratio (PR) schedule of reinforcement. We performed a follow-up experiment that included the same viral manipulation and testing, but the reinforcer was switched to food pellets. We found that NAc miR-495 overexpression reduces cocaine self-administration on a PR, but not an FR5, schedule of reinforcement. We found no effects of miR-495 overexpression on food reinforcement. These data suggest that NAc miR-495 regulates genes involved in motivation for cocaine, but not general motivation based on the data with food reinforcement. Future studies will seek to determine the specific target genes responsible for our behavioral effects.
ContributorsGalles, Nick (Author) / Neisewander, Janet (Thesis director) / Bastle, Ryan (Committee member) / Foster, M. (Committee member) / Barrett, The Honors College (Contributor)
Created2016-05
Description
While not officially recognized as an addictive activity by the Diagnostic and Statistical Manual of Mental Disorders, video game addiction has well-documented resources pointing to its effects on physiological and mental health for both addict and those close to the addict. With the rise of eSports, treating video game addiction has become trickier as a passionate and growing fan base begins to act as a culture not unlike traditional sporting. These concerns call for a better understanding of what constitutes a harmful addiction to video games as its heavy practice becomes more financially viable and accepted into mainstream culture.
ContributorsGohil, Abhishek Bhagirathsinh (Author) / Kashiwagi, Dean (Thesis director) / Kashiwagi, Jacob (Committee member) / Barrett, The Honors College (Contributor) / Computer Science and Engineering Program (Contributor)
Created2015-05
Description
This paper goes through a two-pronged approach in the attempt to understand E-Sports, entertainment gaming, and the creation of the E-Sports bar/Barcade. The first portion aims to explain and quantify the growth of electronic sports (or E-sports). This new craze has been growing immensely in the past 5 years, by viewership and by monetary endorsements. With these changes and growth patterns, we then move on to explain one of the many niche markets that has been created from the growth of E-sports and entertainment gaming. Through our experience in the field, we have evaluated 8 E-sports bars and Barcades in order to confirm their viability in the marketplace. Through our worldwide research we have found that E-sports will continue to grow and that Barcades will not only be viable, but will be a competitive market in the next 10-20 years.
ContributorsNist, Nicholas (Co-author) / Hester, James (Co-author) / Brooks, Dan (Thesis director) / Forss, Brennan (Committee member) / Barrett, The Honors College (Contributor) / Department of Economics (Contributor) / Department of Supply Chain Management (Contributor) / W. P. Carey School of Business (Contributor) / Department of Psychology (Contributor)
Created2015-05
Description
This thesis consisted in taking the preliminary steps in starting a business. Teamed up with a seasoned entrepreneur, we created a thorough Business Plan, Pro Forma and Investor presentation documents, all of which have been and still are being used in the process of creating the business. The business is in the competitive eSports industry, and involved camps and leagues targeted to youth ages 8-15. We have launched the first camp, and are in talks with investors and key strategic partners.
ContributorsHeiler, George (Co-author) / Gaynor, Tristan (Co-author) / Murphy, Kevin (Co-author) / Neck, Christopher (Thesis director) / McLurg, Dave (Committee member) / Department of Information Systems (Contributor) / Department of Supply Chain Management (Contributor) / Department of Finance (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Cocaine is a highly addictive psychostimulant that is widely used around the world. It is far more cost effective to curb this problem through treatment than by any other method as medicinal drug treatment is 15 times more effective than law enforcement at reducing the societal costs of cocaine use as determine by RAND corp. In a previous paper from our lab, it was found that via virally mediated introduction of additional 5-HT1B receptors into the nucleus accumbens there was a leftward shift in the cocaine intake dose-response curve in animals that were self-administering cocaine by pressing a lever. These findings suggest that 5-HT1B receptor action enhances the reinforcing effects of cocaine. However, when animals were given a 21-day period of prolonged abstinence and then tested for cocaine intake, it was determined that 5-HT1B receptor action had the opposite effect of decreasing cocaine intake presumably due to a decrease in the reinforcing effects of cocaine: [16]. The experiment in the current paper was devised to further test this finding via pharmacological means using the 5-HT1B agonist CP 94253 to increase stimulation of 5-HT1B receptors. Animals were trained to self-administer by pressing a lever on fixed ratio schedules of cocaine reinforcement given at 0.75 mg/kg and 0.075 mg/kg doses of cocaine. These doses allowed us to examine changes in self-administration on both the ascending and descending limbs of the inverted u-shaped cocaine dose-effect curve. Our results indicated that in animals given CP 94253 exhibited a decrease in responding on both the ascending and descending limbs of the dose response curve demonstrating a downward shift after prolonged abstinence. These exciting results suggest that the agonist decreases cocaine intake, and therefore, the agonist may be a useful treatment for cocaine dependence.
ContributorsYanamandra, Krishna Teja (Author) / Neisewander, Janet (Thesis director) / Goldstein, Elliott (Committee member) / Pentkowski, Nathan (Committee member) / Barrett, The Honors College (Contributor)
Created2013-05
Description
Substance abuse disorders affect 15.3 million people worldwide. The field has primarily focused on dopaminergic drugs as treatments for substance use disorders. However, recent work has demonstrated the potential of serotonergic compounds to treat substance abuse. Specifically, the serotonin 1B receptor (5-HT1BR), a Gi-coupled receptor located throughout the mesocorticolimbic dopamine system, has been implicated in the incentive motivational and rewarding effects of cocaine. Our research suggests that the stimulation of 5-HT1BRs produces different effects at various time points in the addiction cycle. During maintenance of chronic cocaine administration, 5-HT1BR stimulation has a facilitative effect on the reinforcing properties of cocaine. However 5-HT1BR stimulation exhibits inhibitory effects on reinforcement during prolonged abstinence from cocaine. The aim of this study was to examine the possibility of a switch in the functional role of 5-HT1BRs in the locomotor effects of cocaine at different time points of chronic cocaine administration in mice. We found that the 5-HT1BR agonist CP 94,253 increased locomotor activity in mice tested one day after the last chronic cocaine administration session regardless of whether the chronic treatment was cocaine or saline and regardless of challenge injection (i.e., cocaine or saline). Yet after abstinence, CP 94,253 induced a decrease in locomotor activity in mice challenged with saline and attenuated cocaine-induced locomotion relative to cocaine challenge after vehicle pretreatment. These findings suggest that a switch in the functional role of 5-HT1BR is observed at different stages of the addiction cycle and further suggest that clinical applications of drugs acting on 5-HT1BR should consider these effects.
ContributorsBrunwasser, Samuel Joshua (Author) / Neisewander, Janet (Thesis director) / Pentkowski, Nathan (Committee member) / Der-Ghazarian, Taleen (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor) / Department of Psychology (Contributor)
Created2014-05
Description
The serotonin (5-hydroxytryptamine, 5-HT) system is implicated in the study of drug addiction. Of the 14 known serotonin receptor subtypes, the 5-HT7R is the most recently discovered and, therefore, one of the least rigorously studied. However, the 5-HT7R has been shown to play a role in multiple psychiatric conditions, including depression, anxiety, and alcoholism. This is not surprising, as the 5-HT7R is expressed in brain regions associated with emotion and reward, such as the amygdala, dorsal raphe nucleus, and striatum. MC-RG19 is a novel 5-HT7R antagonist which has >114-fold selectivity for the 5-HT7 over other serotonin receptors. This compound was developed by our collaborators at the Temple University School of Pharmacy. Due to this specificity, and the implications of the 5-HT7 in behavior, we hypothesized that MC-RG19 would have an effect on addiction-related behaviors. We investigated the effects of MC-RG19 on spontaneous locomotion, cue-induced reinstatement, and cocaine/sucrose multiple schedule self-administration. We observed a dose-dependent decrease in spontaneous locomotor activity with significance at a MC-RG19 dose of 10 mg/kg. A dose of 5.6 mg/kg, which did not significantly decrease locomotion, significantly reduces cocaine-seeking behavior (active lever pressing) in response to the reintroduction of drug-paired cues after a period of extinction. No dose (3, 5.6, or 10 mg/kg) produced a significant effect on a multiple schedule of self-administration with alternating availability of sucrose and cocaine as the reinforcer. These results indicate that MC-RG19 has an effect on the incentive \u2014 motivational properties of reward-paired cues.
ContributorsCarlson, Andrew Kenneth (Author) / Neisewander, Janet (Thesis director) / Gipson-Reichardt, Cassandra (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Abstract Cocaine is highly addictive because it exacerbates the action responsible for creating the feeling of "reward," which is controlled by the neurotransmitter dopamine. Dopamine receptors can be divided into five subtypes: D1, D2, D3, D4, and D5. The localization of D3 receptors is restricted to the mesolimbic pathway, which is often called the "reward pathway." This pathway is associated with emotions, motivation, and behavior. There is evidence that these receptors are upregulated in response to the repeated use of psychostimulants, such as cocaine, making these receptors a potential target for pharmaceutical therapeutics for drug addiction. In the present study, two compounds selective for D3 receptors, MC-250041 and LS-3-134, were examined for their effects on spontaneous and cocaine-primed locomotor activity. The present study also aimed to examine the effects of MC-250041 and LS-3-134 on the number of lever presses and infusions under a progressive ratio (PR) schedule when subjects are trained to self-administer cocaine within an operant conditioning chamber. Based on the present research on D3 receptor compounds and D3Rs, I hypothesized that pretreatment with MC-250041 or LS-3-134 decreases cocaine self-administration under a progressive ratio (PR) schedule of cocaine reinforcement at doses that would have no effect on locomotor activity. The results showed no significant effects on spontaneous or cocaine-primed locomotor activity following an injection of MC-250041 (1, 3, 5.6 mg/kg IP). Similarly, there was no change in the amount of lever presses or drug infusions within an operant conditioning chamber at any of the examined doses of MC-250041 (3, 5.6, 10 mg/kg IP) during self-administration. LS-3-134 decreased cocaine-primed locomotor activity, as well as lever presses and infusions during self-administration at the 5.6 mg/kg dose; however, there was no effect on spontaneous locomotor activity at any of the examined doses (1, 3.2, 5.6 mg/kg IP). In conclusion, the results of the study suggest that LS-3-134 effectively reduced motivation for cocaine at the 5.6 mg/kg dose; whereas, MC-250041 was unsuccessful at warranting any significant effect on motivation for cocaine at any of the examined doses.
ContributorsMendoza, Rachel Ann (Author) / Neisewander, Janet (Thesis director) / Olive, Foster (Committee member) / Powell, Greg (Committee member) / School of Social Transformation (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2017-05